Erratum: History and progress of hypotheses and clinical trials for Alzheimer’s disease (Signal Transduction and Targeted Therapy, (2019), 10.1038/s41392-019-0063-8);History and progress of hypotheses and clinical trials for alzheimer’s disease

Signal Transduction and Targeted Therapy

Volumn 4, Issue 1, 2019, Pages

  Liu, Pei Pei ^a   Xie, Yi ^a   Meng, Xiao Yan ^a   Kang, Jian Sheng ^a  

^a THE FIRST AFFILIATED HOSPITAL OF ZHENGZHOU UNIVERSITY   (China)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 85076045267     PISSN: 20959907     EISSN: 20593635     Source Type: Journal    
DOI: 10.1038/s41392-019-0071-8     Document Type: Erratum

References (457)

1. Blennow, K., de Leon, M. J. & Zetterberg, H. Alzheimer’s disease. Lancet 368, 387–403 (2006).
2. Nelson, P. T., Braak, H. & Markesbery, W. R. Neuropathology and cognitive impairment in Alzheimer disease: a complex but coherent relationship. J. Neuropathol. Exp. Neurol. 68, 1–14 (2009).
3. Brookmeyer, R., Gray, S. & Kawas, C. Projections of Alzheimer’s disease in the United States and the public health impact of delaying disease onset. Am. J. Public Health 88, 1337–1342 (1998).
4. Breteler, M. M., van den Ouweland, F. A., Grobbee, D. E. & Hofman, A. A community-based study of dementia: the Rotterdam elderly study. Neuroepidemiology 11(Suppl 1), 23–28 (1992).
5. Ferri, C. P. et al. Global prevalence of dementia: a Delphi consensus study. Lancet 366, 2112–2117 (2005).
6. Weiner, M. W. et al. The Alzheimer’s Disease Neuroimaging Initiative: a review of papers published since its inception. Alzheimers Dement. 8, S1–S68 (2012).
7. Launer, L. J. Overview of incidence studies of dementia conducted in Europe. Neuroepidemiology 11(Suppl 1), 2–13 (1992).
8. Kidd, M. Paired helical filaments in electron microscopy of Alzheimer’s disease. Nature 197, 192–193 (1963).
9. Terry, R. D. The fine structure of neurofibrillary tangles in Alzheimer’s disease. J. Neuropathol. Exp. Neurol. 22, 629–642 (1963).
10. Hardy, J. A hundred years of Alzheimer’s disease research. Neuron 52, 3–13 (2006).
11. Ertekin-Taner, N. Genetics of Alzheimer’s disease: a centennial review. Neurol. Clin. 25, 611–667 (2007). v.
12. Canter, R. G., Penney, J. & Tsai, L. H. The road to restoring neural circuits for the treatment of Alzheimer’s disease. Nature 539, 187–196 (2016).
13. Reitz, C. & Mayeux, R. Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers. Biochemical Pharmacol. 88, 640–651 (2014).
14. Bateman, R. J. et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. New Engl. J. Med. 367, 795–804 (2012).
15. McInnes, J. Insights on altered mitochondrial function and dynamics in the pathogenesis of neurodegeneration. Transl. Neurodegener. 2, 12 (2013).
16. Cuyvers, E. & Sleegers, K. Genetic variations underlying Alzheimer’s disease: evidence from genome-wide association studies and beyond. Lancet Neurol. 15, 857–868 (2016).
17. Lambert, J. C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat. Genet. 45, 1452–1458 (2013).
18. Goate, A. et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349, 704–706 (1991).
19. Saunders, A. M. et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 43, 1467–1472 (1993).
20. Rogaev, E. I. et al. Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature 376, 775–778 (1995).
21. Sherrington, R. et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375, 754–760 (1995).
22. Corder, E. H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921–923 (1993).
23. Bu, G. Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nat. Rev. Neurosci. 10, 333–344 (2009).
24. Farrer, L. A. et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer disease meta analysis consortium. JAMA 278, 1349–1356 (1997).
25. Liu, C. C., Liu, C. C., Kanekiyo, T., Xu, H. & Bu, G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat. Rev. Neurol. 9, 106–118 (2013).
26. Strittmatter, W. J. et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc. Natl Acad. Sci. USA 90, 1977–1981 (1993).
27. Poirier, J. et al. Apolipoprotein E polymorphism and Alzheimer’s disease. Lancet 342, 697–699 (1993).
28. Ma, J., Brewer, H. B. Jr. & Potter, H. Alzheimer A beta neurotoxicity: promotion by antichymotrypsin, ApoE4; inhibition by A beta-related peptides. Neurobiol. Aging 17, 773–780 (1996).
29. Tiraboschi, P. et al. Impact of APOE genotype on neuropathologic and neuro-chemical markers of Alzheimer disease. Neurology 62, 1977–1983 (2004).
30. Hoe, H. S. et al. Interaction of reelin with amyloid precursor protein promotes neurite outgrowth. J. Neurosci. 29, 7459–7473 (2009).
31. Davies, P. & Maloney, A. J. Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet 2, 1403 (1976).
32. Selkoe, D. J. The molecular pathology of Alzheimer’s disease. Neuron 6, 487–498 (1991).
33. Hardy, J. & Allsop, D. Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol. Sci. 12, 383–388 (1991).
34. Frost, B., Jacks, R. L. & Diamond, M. I. Propagation of tau misfolding from the outside to the inside of a cell. J. Biol. Chem. 284, 12845–12852 (2009).
35. Swerdlow, R. H. & Khan, S. M. A “mitochondrial cascade hypothesis” for sporadic Alzheimer’s disease. Med. Hypotheses 63, 8–20 (2004).
36. Mattson, M. P. et al. beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J. Neurosci. 12, 376–389 (1992).
37. McGeer, P. L. & Rogers, J. Anti-inflammatory agents as a therapeutic approach to Alzheimer’s disease. Neurology 42, 447–449 (1992).
38. Iadecola, C. Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat. Rev. Neurosci. 5, 347–360 (2004).
39. Bush, A. I. et al. Rapid induction of Alzheimer A beta amyloid formation by zinc. Science 265, 1464–1467 (1994).
40. Deane, R. et al. LRP/amyloid beta-peptide interaction mediates differential brain efflux of Abeta isoforms. Neuron 43, 333–344 (2004).
41. Silverman, J. M. et al. The consortium to establish a registry for Alzheimer’s disease (CERAD). Part VI. Family history assessment: a multicenter study of first-degree relatives of Alzheimer’s disease probands and nondemented spouse controls. Neurology 44, 1253–1259 (1994).
42. Launer, L. J. et al. Midlife blood pressure and dementia: the Honolulu-Asia aging study. Neurobiol. Aging 21, 49–55 (2000).
43. Osorio, R. S. et al. Greater risk of Alzheimer’s disease in older adults with insomnia. J. Am. Geriatrics Soc. 59, 559–562 (2011).
44. Whitmer, R. A., Gunderson, E. P., Barrett-Connor, E., Quesenberry, C. P. Jr. & Yaffe, K. Obesity in middle age and future risk of dementia: a 27 year longitudinal population based study. BMJ 330, 1360 (2005).
45. Butterfield, D. A. & Halliwell, B. Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat. Rev. Neurosci. 20, 148–160 (2019).
46. Martins, R. N. et al. Alzheimer’s disease: a journey from amyloid peptides and oxidative stress, to biomarker technologies and disease prevention strategies-gains from AIBL and DIAN cohort study. J. Alzheimers Dis. 62, 965–992 (2018).
47. Mukherjee, S. et al. Genetic data and cognitively defined late-onset Alzheimer’s disease subgroups. Mol. Psychiatry, https://doi.org/10.1038/s41380-018-0298-8 (2018).
48. Aupperle, P. M. Navigating patients and caregivers through the course of Alzheimer’s disease. J. Clin. Psychiatry 67(Suppl 3), 8–14 (2006). quiz23.
49. Qian, X., Hamad, B. & Dias-Lalcaca, G. The Alzheimer disease market. Nat. Rev. Drug Discov. 14, 675–676 (2015).
50. Francis, P. T., Palmer, A. M., Snape, M. & Wilcock, G. K. The cholinergic hypothesis of Alzheimer’s disease: a review of progress. J. Neurol. Neurosurg. Psychiatry 66, 137–147 (1999).
51. Fotiou, D., Kaltsatou, A., Tsiptsios, D. & Nakou, M. Evaluation of the cholinergic hypothesis in Alzheimer’s disease with neuropsychological methods. Aging Clin. Exp. Res. 27, 727–733 (2015).
52. Ferreira-Vieira, T. H., Guimaraes, I. M., Silva, F. R. & Ribeiro, F. M. Alzheimer’s disease: targeting the cholinergic system. Curr. Neuropharmacol. 14, 101–115 (2016).
53. Bowen, D. M., Smith, C. B., White, P. & Davison, A. N. Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiotrophies. Brain 99, 459–496 (1976).
54. White, P. et al. Neocortical cholinergic neurons in elderly people. Lancet 1, 668–671 (1977).
55. Perry, E. K., Perry, R. H., Blessed, G. & Tomlinson, B. E. Necropsy evidence of central cholinergic deficits in senile dementia. Lancet 1, 189 (1977).
56. Hakansson, L. Mechanism of action of cholinesterase inhibitors in Alzheimer’s disease. Acta Neurol. Scand. Suppl. 149, 7–9 (1993).
57. Anand, P. & Singh, B. A review on cholinesterase inhibitors for Alzheimer’s disease. Arch. Pharmacal Res. 36, 375–399 (2013).
58. O'Regan, J., Lanctot, K. L., Mazereeuw, G. & Herrmann, N. Cholinesterase inhibitor discontinuation in patients with Alzheimer’s disease: a meta-analysis of randomized controlled trials. J. Clin. Psychiatry 76, e1424–e1431 (2015).
59. Deardorff, W. J., Feen, E. & Grossberg, G. T. The use of cholinesterase inhibitors across all stages of Alzheimer’s disease. Drugs Aging 32, 537–547 (2015).
60. Davis, K. L. & Powchik, P. Tacrine. Lancet 345, 625–630 (1995).
61. Bullock, R. et al. Rivastigmine and donepezil treatment in moderate to moderately-severe Alzheimer’s disease over a 2-year period. Curr. Med. Res. Opin. 21, 1317–1327 (2005).
62. Wilcock, G. et al. A long-term comparison of galantamine and donepezil in the treatment of Alzheimer’s disease. Drugs aging 20, 777–789 (2003).
63. Mintzer, J. E. & Kershaw, P. The efficacy of galantamine in the treatment of Alzheimer’s disease: comparison of patients previously treated with acetylcholinesterase inhibitors to patients with no prior exposure. Int. J. Geriatr. psychiatry 18, 292–297 (2003).
64. Knight, R., Khondoker, M., Magill, N., Stewart, R. & Landau, S. A systematic review and meta-analysis of the effectiveness of acetylcholinesterase inhibitors and memantine in treating the cognitive symptoms of dementia. Dement. Geriatr. Cogn. Disord. 45, 131–151 (2018).
65. Lon, S. S. A critical review of cholinesterase inhibitors as a treatment modality in Alzheimer’s disease. Dialogues Clin. Neurosci. 2, 111–128 (2000).
66. Dementia – caring, ethics, ethnical and economical aspects: a systematic review. Stockholm: Swedish Council on Health Technology Assessment (SBU). (2008).
67. Drugs for Alzheimer’s disease: best avoided. No therapeutic advantage. Prescrire Int. 21, 150 (2012).
68. Hardy, J. & Selkoe, D. J. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297, 353–356 (2002).
69. Quon, D. et al. Formation of beta-amyloid protein deposits in brains of transgenic mice. Nature 352, 239–241 (1991).
70. Bennett, D. A. et al. Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology 66, 1837–1844 (2006).
71. De Meyer, G. et al. Diagnosis-independent Alzheimer disease biomarker signature in cognitively normal elderly people. Arch. Neurol. 67, 949–956 (2010).
72. Fagan, A. M. et al. Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults. Arch. Neurol. 64, 343–349 (2007).
73. Gomperts, S. N. et al. Imaging amyloid deposition in Lewy body diseases. Neurology 71, 903–910 (2008).
74. Glenner, G. G. & Wong, C. W. Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochemical Biophysical Res. Commun. 120, 885–890 (1984).
75. Kang, J. et al. The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 325, 733–736 (1987).
76. St George-Hyslop, P. H. et al. The genetic defect causing familial Alzheimer’s disease maps on chromosome 21. Science 235, 885–890 (1987).
77. Mullan, M. et al. A pathogenic mutation for probable Alzheimer’s disease in the APP gene at the N-terminus of beta-amyloid. Nat. Genet. 1, 345–347 (1992).
78. Di Fede, G. et al. A recessive mutation in the APP gene with dominant-negative effect on amyloidogenesis. Science 323, 1473–1477 (2009).
79. Karran, E., Mercken, M. & De Strooper, B. The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat. Rev. Drug Discov. 10, 698–712 (2011).
80. Sisodia, S. S., Koo, E. H., Beyreuther, K., Unterbeck, A. & Price, D. L. Evidence that beta-amyloid protein in Alzheimer’s disease is not derived by normal processing. Science 248, 492–495 (1990).
81. Jonsson, T. et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature 488, 96–99 (2012).
82. Yankner, B. A., Duffy, L. K. & Kirschner, D. A. Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science 250, 279–282 (1990).
83. Wang, J., Dickson, D. W., Trojanowski, J. Q. & Lee, V. M. The levels of soluble versus insoluble brain Abeta distinguish Alzheimer’s disease from normal and pathologic aging. Exp. Neurol. 158, 328–337 (1999).
84. Walsh, D. M. et al. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535–539 (2002).
85. Lewis, J. et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293, 1487–1491 (2001).
86. Palop, J. J. et al. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer’s disease. Neuron 55, 697–711 (2007).
87. Lim, H. K. et al. Regional amyloid burden and intrinsic connectivity networks in cognitively normal elderly subjects. Brain 137, 3327–3338 (2014).
88. Lim, Y. Y. et al. Effect of amyloid on memory and non-memory decline from preclinical to clinical Alzheimer’s disease. Brain 137, 221–231 (2014).
89. Lim, Y. Y. et al. Abeta and cognitive change: examining the preclinical and prodromal stages of Alzheimer’s disease. Alzheimer’s Dement. 10, 743–751.e741 (2014).
90. Knopman, D. S. et al. Short-term clinical outcomes for stages of NIA-AA preclinical Alzheimer disease. Neurology 78, 1576–1582 (2012).
91. Vos, S. J. et al. Preclinical Alzheimer’s disease and its outcome: a longitudinal cohort study. Lancet Neurol. 12, 957–965 (2013).
92. Golde, T. E. Open questions for Alzheimer’s disease immunotherapy. Alzheimer’s. Res. Ther. 6, 3 (2014).
93. Honig, L. S. et al. Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease. New Engl. J. Med. 378, 321–330 (2018).
94. Ostrowitzki, S. et al. A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimer’s. Res. Ther. 9, 95 (2017).
95. Egan, M. F. et al. Randomized trial of verubecestat for mild-to-moderate Alzheimer’s disease. New Engl. J. Med. 378, 1691–1703 (2018).
96. Doody, R. S. et al. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. New Engl. J. Med. 369, 341–350 (2013).
97. Wolfe, M. S. Inhibition and modulation of gamma-secretase for Alzheimer’s disease. Neurotherapeutics 5, 391–398 (2008).
98. Braak, H. & Braak, E. Evolution of the neuropathology of Alzheimer’s disease. Acta Neurol. Scand. Suppl. 165, 3–12 (1996).
99. Braak, E. et al. Neuropathology of Alzheimer’s disease: what is new since A. Alzheimer? Eur. Arch. Psychiatry Clin. Neurosci. 249(Suppl 3), 14–22 (1999).
100. Nukina, N. & Ihara, Y. One of the antigenic determinants of paired helical filaments is related to tau protein. J. Biochem. 99, 1541–1544 (1986).
101. Grundke-Iqbal, I. et al. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J. Biol. Chem. 261, 6084–6089 (1986).
102. Kosik, K. S., Joachim, C. L. & Selkoe, D. J. Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc. Natl Acad. Sci. USA 83, 4044–4048 (1986).
103. Grundke-Iqbal, I. et al. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc. Natl Acad. Sci. USA 83, 4913–4917 (1986).
104. Clavaguera, F. et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat. Cell Biol. 11, 909–913 (2009).
105. Goedert, M., Wischik, C. M., Crowther, R. A., Walker, J. E. & Klug, A. Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc. Natl Acad. Sci. USA 85, 4051–4055 (1988).
106. Lee, G., Cowan, N. & Kirschner, M. The primary structure and heterogeneity of tau protein from mouse brain. Science 239, 285–288 (1988).
107. Goedert, M., Spillantini, M. G., Jakes, R., Rutherford, D. & Crowther, R. A. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron 3, 519–526 (1989).
108. Andreadis, A., Brown, W. M. & Kosik, K. S. Structure and novel exons of the human tau gene. Biochemistry 31, 10626–10633 (1992).
109. Adams, S. J., DeTure, M. A., McBride, M., Dickson, D. W. & Petrucelli, L. Three repeat isoforms of tau inhibit assembly of four repeat tau filaments. PloS ONE 5, e10810 (2010).
110. Allen, B. et al. Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J. Neurosci. 22, 9340–9351 (2002).
111. Probst, A. et al. Axonopathy and amyotrophy in mice transgenic for human four-repeat tau protein. Acta Neuropathol. 99, 469–481 (2000).
112. Merrick, S. E., Trojanowski, J. Q. & Lee, V. M. Selective destruction of stable microtubules and axons by inhibitors of protein serine/threonine phosphatases in cultured human neurons. J. Neurosci. 17, 5726–5737 (1997).
113. Buee, L., Bussiere, T., Buee-Scherrer, V., Delacourte, A. & Hof, P. R. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res. Brain Res. Rev. 33, 95–130 (2000).
114. Liu, F., Iqbal, K., Grundke-Iqbal, I., Hart, G. W. & Gong, C. X. O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer’s disease. Proc. Natl Acad. Sci. USA 101, 10804–10809 (2004).
115. Lefebvre, T. et al. Evidence of a balance between phosphorylation and O-GlcNAc glycosylation of Tau proteins-a role in nuclear localization. Biochimica et. Biophysica Acta 1619, 167–176 (2003).
116. Lee, G. et al. Phosphorylation of tau by fyn: implications for Alzheimer’s disease. J. Neurosci. 24, 2304–2312 (2004).
117. Gong, C. X., Liu, F., Grundke-Iqbal, I. & Iqbal, K. Post-translational modifications of tau protein in Alzheimer's disease. J. Neural Transm. 112, 813–838 (2005).
118. Arriagada, P. V., Marzloff, K. & Hyman, B. T. Distribution of Alzheimer-type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer’s disease. Neurology 42, 1681–1688 (1992).
119. Wittmann, C. W. et al. Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles. Science 293, 711–714 (2001).
120. Pastor, P. et al. Apolipoprotein Eepsilon4 modifies Alzheimer’s disease onset in an E280A PS1 kindred. Ann. Neurol. 54, 163–169 (2003).
121. Bales, K. R. et al. amyloid, and Alzheimer disease. Mol. Interventions 2, 363–375, 339 (2002).
122. DeMattos, R. B. et al. ApoE and clusterin cooperatively suppress Abeta levels and deposition: evidence that ApoE regulates extracellular Abeta metabolism in vivo. Neuron 41, 193–202 (2004).
123. Fagan, A. M. et al. Human and murine ApoE markedly alters A beta metabolism before and after plaque formation in a mouse model of Alzheimer’s disease. Neurobiol. Dis. 9, 305–318 (2002).
124. Brecht, W. J. et al. Neuron-specific apolipoprotein e4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. J. Neurosci. 24, 2527–2534 (2004).
125. Harris, F. M. et al. Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer’s disease-like neurodegeneration and behavioral deficits in transgenic mice. Proc. Natl Acad. Sci. USA 100, 10966–10971 (2003).
126. Gibb, G. M. et al. Differential effects of apolipoprotein E isoforms on phosphorylation at specific sites on tau by glycogen synthase kinase-3 beta identified by nano-electrospray mass spectrometry. FEBS Lett. 485, 99–103 (2000).
127. Phiel, C. J., Wilson, C. A., Lee, V. M. & Klein, P. S. GSK-3alpha regulates production of Alzheimer’s disease amyloid-beta peptides. Nature 423, 435–439 (2003).
128. Su, Y. et al. Lithium, a common drug for bipolar disorder treatment, regulates amyloid-beta precursor protein processing. Biochemistry 43, 6899–6908 (2004).
129. Rapoport, M., Dawson, H. N., Binder, L. I., Vitek, M. P. & Ferreira, A. Tau is essential to beta-amyloid-induced neurotoxicity. Proc. Natl Acad. Sci. USA 99, 6364–6369 (2002).
130. Gong, L. et al. Iron dyshomeostasis induces binding of APP to BACE1 for amyloid pathology, and impairs APP/Fpn1 complex in microglia: implication in pathogenesis of cerebral microbleeds. Cell Transplant. https://doi.org/10.1177/0963689719831707 (2019).
131. Xian-hui, D. et al. Age-related changes of brain iron load changes in the frontal cortex in APPswe/PS1DeltaE9 transgenic mouse model of Alzheimer's disease. J. Trace Elements Med. Biol. 30, 118–123 (2015).
132. Li, X. et al. Enduring elevations of hippocampal amyloid precursor protein and iron are features of beta-amyloid toxicity and are mediated by tau. Neurotherapeutics 12, 862–873 (2015).
133. Tuo, Q. Z. et al. Tau-mediated iron export prevents ferroptotic damage after ischemic stroke. Mol. Psychiatry 22, 1520–1530 (2017).
134. Lei, P. et al. Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nat. Med. 18, 291–295 (2012).
135. Boutajangout, A., Ingadottir, J., Davies, P. & Sigurdsson, E. M. Passive immunization targeting pathological phospho-tau protein in a mouse model reduces functional decline and clears tau aggregates from the brain. J. Neurochem. 118, 658–667 (2011).
136. Asuni, A. A., Boutajangout, A., Quartermain, D. & Sigurdsson, E. M. Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. J. Neurosci. 27, 9115–9129 (2007).
137. Wilcock, G. K. et al. Potential of Low dose leuco-methylthioninium bis(hydro-methanesulphonate) (LMTM) monotherapy for treatment of mild Alzheimer’s disease: cohort analysis as modified primary outcome in a phase III clinical trial. J. Alzheimer’s. Dis. 61, 435–457 (2018).
138. Novak, P. et al. FUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer’s disease. Alzheimer’s. Res. Ther. 10, 108 (2018).
139. Trifunovic, A. et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417–423 (2004).
140. Kujoth, G. C. et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309, 481–484 (2005).
141. Ross, J. M. et al. Germline mitochondrial DNA mutations aggravate ageing and can impair brain development. Nature 501, 412–415 (2013).
142. Jones, D. P. Redefining oxidative stress. Antioxid. Redox Signal. 8, 1865–1879 (2006).
143. Hauptmann, N., Grimsby, J., Shih, J. C. & Cadenas, E. The metabolism of tyramine by monoamine oxidase A/B causes oxidative damage to mitochondrial DNA. Arch. Biochem. Biophys. 335, 295–304 (1996).
144. Di Meo, S., Reed, T. T., Venditti, P. & Victor, V. M. Role of ROS and RNS sources in physiological and pathological conditions. Oxid. Med. Cell. Longev. 2016, 1245049 (2016).
145. Hirai, K. et al. Mitochondrial abnormalities in Alzheimer’s disease. J. Neurosci. 21, 3017–3023 (2001).
146. Ray, P. D., Huang, B. W. & Tsuji, Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell. Signal. 24, 981–990 (2012).
147. Holmstrom, K. M. & Finkel, T. Cellular mechanisms and physiological consequences of redox-dependent signalling. Nat. Rev. Mol. Cell Biol. 15, 411–421 (2014).
148. Uttara, B., Singh, A. V., Zamboni, P. & Mahajan, R. T. Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr. Neuropharmacol. 7, 65–74 (2009).
149. Gibson, G. E., Sheu, K. F. & Blass, J. P. Abnormalities of mitochondrial enzymes in Alzheimer disease. J. Neural Transm. 105, 855–870 (1998).
150. Chandrasekaran, K. et al. Impairment in mitochondrial cytochrome oxidase gene expression in Alzheimer disease. Brain Res. Mol. Brain Res. 24, 336–340 (1994).
151. Cottrell, D. A., Blakely, E. L., Johnson, M. A., Ince, P. G. & Turnbull, D. M. Mitochondrial enzyme-deficient hippocampal neurons and choroidal cells in AD. Neurology 57, 260–264 (2001).
152. Maurer, I., Zierz, S. & Moller, H. J. A selective defect of cytochrome c oxidase is present in brain of Alzheimer disease patients. Neurobiol. Aging 21, 455–462 (2000).
153. Nagy, Z., Esiri, M. M., LeGris, M. & Matthews, P. M. Mitochondrial enzyme expression in the hippocampus in relation to Alzheimer-type pathology. Acta Neuropathol. 97, 346–354 (1999).
154. Bubber, P., Haroutunian, V., Fisch, G., Blass, J. P. & Gibson, G. E. Mitochondrial abnormalities in Alzheimer brain: mechanistic implications. Ann. Neurol. 57, 695–703 (2005).
155. Manczak, M. et al. Mitochondria are a direct site of A beta accumulation in Alzheimer’s disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum. Mol. Genet. 15, 1437–1449 (2006).
156. Kamat, P. K. et al. Mechanism of oxidative stress and synapse dysfunction in the pathogenesis of Alzheimer’s disease: understanding the therapeutics strategies. Mol. Neurobiol. 53, 648–661 (2016).
157. Snyder, E. M. et al. Regulation of NMDA receptor trafficking by amyloid-beta. Nat. Neurosci. 8, 1051–1058 (2005).
158. Bezprozvanny, I. & Mattson, M. P. Neuronal calcium mishandling and the pathogenesis of Alzheimer’s disease. Trends Neurosci. 31, 454–463 (2008).
159. Gatz, M. et al. Role of genes and environments for explaining Alzheimer disease. Arch. Gen. Psychiatry 63, 168–174 (2006).
160. Lunnon, K. & Mill, J. Epigenetic studies in Alzheimer’s disease: current findings, caveats, and considerations for future studies. Am. J. Med. Genet. B Neu-ropsychiatr. Genet. 162b, 789–799 (2013).
161. Gjoneska, E. et al. Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer’s disease. Nature 518, 365–369 (2015).
162. Nativio, R. et al. Publisher Correction: Dysregulation of the epigenetic landscape of normal aging in Alzheimer’s disease. Nat. Neurosci. 21, 1018 (2018).
163. Zhang, K. et al. Targeted proteomics for quantification of histone acetylation in Alzheimer’s disease. Proteomics 12, 1261–1268 (2012).
164. Matilainen, O., Quiros, P. M. & Auwerx, J. Mitochondria and epigenetics: crosstalk in homeostasis and stress. Trends Cell Biol. 27, 453–463 (2017).
165. Mastroeni, D., McKee, A., Grover, A., Rogers, J. & Coleman, P. D. Epigenetic differences in cortical neurons from a pair of monozygotic twins discordant for Alzheimer’s disease. PloS ONE 4, e6617 (2009).
166. Mastroeni, D. et al. Epigenetic changes in Alzheimer’s disease: decrements in DNA methylation. Neurobiol. Aging 31, 2025–2037 (2010).
167. Chouliaras, L. et al. Consistent decrease in global DNA methylation and hydroxymethylation in the hippocampus of Alzheimer’s disease patients. Neurobiol. Aging 34, 2091–2099 (2013).
168. Condliffe, D. et al. Cross-region reduction in 5-hydroxymethylcytosine in Alzheimer’s disease brain. Neurobiol. Aging 35, 1850–1854 (2014).
169. Teperino, R., Schoonjans, K. & Auwerx, J. Histone methyl transferases and demethylases; can they link metabolism and transcription? Cell Metab. 12, 321–327 (2010).
170. Chiang, P. K. et al. S-Adenosylmethionine and methylation. FASEB J. 10, 471–480 (1996).
171. Figueroa, M. E. et al. Leukemic IDH1 and IDH2 mutations result in a hyper-methylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553–567 (2010).
172. Yan, H. et al. IDH1 and IDH2 mutations in gliomas. New Engl. J. Med. 360, 765–773 (2009).
173. Katewa, S. D., Khanna, A. & Kapahi, P. Mitobolites: the elixir of life. Cell Metab. 20, 8–9 (2014).
174. Sciacovelli, M. et al. Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Nature 537, 544–547 (2016).
175. Hino, S. et al. FAD-dependent lysine-specific demethylase-1 regulates cellular energy expenditure. Nat. Commun. 3, 758 (2012).
176. Wellen, K. E. et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324, 1076–1080 (2009).
177. Imai, S., Armstrong, C. M., Kaeberlein, M. & Guarente, L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403, 795–800 (2000).
178. Fang, E. F. Mitophagy and NAD(+) inhibit Alzheimer disease. Autophagy 15, 1112–1114 (2019).
179. Lemasters, J. J. Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. Rejuvenation Res. 8, 3–5 (2005).
180. Ryan, B. J., Hoek, S., Fon, E. A. & Wade-Martins, R. Mitochondrial dysfunction and mitophagy in Parkinson's: from familial to sporadic disease. Trends Biochem. Sci. 40, 200–210 (2015).
181. Khalil, B. et al. PINK1-induced mitophagy promotes neuroprotection in Huntington's disease. Cell Death Dis. 6, e1617 (2015).
182. Sun, N., Youle, R. J. & Finkel, T. The Mitochondrial Basis of Aging. Mol. Cell 61, 654–666 (2016).
183. Wong, Y. C. & Holzbaur, E. L. Optineurin is an autophagy receptor for damaged mitochondria in parkin-mediated mitophagy that is disrupted by an ALS-linked mutation. Proc. Natl Acad. Sci. USA 111, E4439–E4448 (2014).
184. Fang, E. F. et al. Mitophagy inhibits amyloid-beta and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nat. Neurosci. 22, 401–412 (2019).
185. Kerr, J. S. et al. Mitophagy and Alzheimer’s Disease: Cellular and Molecular Mechanisms. Trends Neurosci. 40, 151–166 (2017).
186. Lucin, K. M. et al. Microglial beclin 1 regulates retromer trafficking and phagocytosis and is impaired in Alzheimer’s disease. Neuron 79, 873–886 (2013).
187. Chin, R. M. et al. The metabolite alpha-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature 510, 397–401 (2014).
188. Mouchiroud, L. et al. Pyruvate imbalance mediates metabolic reprogramming and mimics lifespan extension by dietary restriction in Caenorhabditis elegans. Aging Cell 10, 39–54 (2011).
189. Williams, D. S., Cash, A., Hamadani, L. & Diemer, T. Oxaloacetate supplementa-tion increases lifespan in Caenorhabditis elegans through an AMPK/FOXO-dependent pathway. Aging Cell 8, 765–768 (2009).
190. Wilkins, H. M. et al. Oxaloacetate enhances neuronal cell bioenergetic fluxes and infrastructure. J. Neurochem. 137, 76–87 (2016).
191. Wilkins, H. M. et al. Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis. Hum. Mol. Genet. 23, 6528–6541 (2014).
192. Swerdlow, R. H., Bothwell, R., Hutfles, L., Burns, J. M. & Reed, G. A. Tolerability and pharmacokinetics of oxaloacetate 100 mg capsules in Alzheimer’s subjects. BBA Clin. 5, 120–123 (2016).
193. Khachaturian, Z. S. Calcium, membranes, aging, and Alzheimer’s disease. Introduction and overview. Ann. New Y. Acad. Sci. 568, 1–4 (1989).
194. Marx, J. Alzheimer’s disease. Fresh evidence points to an old suspect: calcium. Science318, 384–385 (2007).
195. Bezprozvanny, I. Calcium signaling and neurodegenerative diseases. Trends Mol. Med. 15, 89–100 (2009).
196. Demuro, A., Parker, I. & Stutzmann, G. E. Calcium signaling and amyloid toxicity in Alzheimer disease. J. Biol. Chem. 285, 12463–12468 (2010).
197. Norris, C. M. et al. Calcineurin triggers reactive/inflammatory processes in astrocytes and is upregulated in aging and Alzheimer’s models. J. Neurosci. 25, 4649–4658 (2005).
198. Abdul, H. M. et al. Cognitive decline in Alzheimer’s disease is associated with selective changes in calcineurin/NFAT signaling. J. Neurosci. 29, 12957–12969 (2009).
199. Berridge, M. J. Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia. Prion 7, 2–13 (2013).
200. FDA approves memantine drug for treating AD. Am. J. Alzheimer’s. Dis. Other Dement. 18, 329–330 (2003).
201. Reisberg, B. et al. Memantine in moderate-to-severe Alzheimer’s disease. New Engl. J. Med. 348, 1333–1341 (2003).
202. Johnson, J. W. & Kotermanski, S. E. Mechanism of action of memantine. Curr. Opin. Pharmacol. 6, 61–67 (2006).
203. Lesne, S. et al. NMDA receptor activation inhibits alpha-secretase and promotes neuronal amyloid-beta production. J. Neurosci. 25, 9367–9377 (2005).
204. Zlokovic, B. V. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57, 178–201 (2008).
205. Moskowitz, M. A., Lo, E. H. & Iadecola, C. The science of stroke: mechanisms in search of treatments. Neuron 67, 181–198 (2010).
206. Guo, S. & Lo, E. H. Dysfunctional cell-cell signaling in the neurovascular unit as a paradigm for central nervous system disease. Stroke 40, S4–S7 (2009).
207. Buee, L. et al. Pathological alterations of the cerebral microvasculature in Alzheimer’s disease and related dementing disorders. Acta Neuropathol 87, 469–480 (1994).
208. Thomas, T., Thomas, G., McLendon, C., Sutton, T. & Mullan, M. beta-Amyloid-mediated vasoactivity and vascular endothelial damage. Nature 380, 168–171 (1996).
209. Iadecola, C. et al. SOD1 rescues cerebral endothelial dysfunction in mice over-expressing amyloid precursor protein. Nat. Neurosci. 2, 157–161 (1999).
210. Niwa, K. et al. Abeta 1-40-related reduction in functional hyperemia in mouse neocortex during somatosensory activation. Proc. Natl Acad. Sci. USA 97, 9735–9740 (2000).
211. Ruitenberg, A. et al. Cerebral hypoperfusion and clinical onset of dementia: the Rotterdam study. Ann. Neurol. 57, 789–794 (2005).
212. Knopman, D. S. & Roberts, R. Vascular risk factors: imaging and neuropathologic correlates. J. Alzheimer’s. Dis. 20, 699–709 (2010).
213. Smith, C. D. et al. Altered brain activation in cognitively intact individuals at high risk for Alzheimer’s disease. Neurology 53, 1391–1396 (1999).
214. Bookheimer, S. Y. et al. Patterns of brain activation in people at risk for Alzheimer's disease. N. Eng. J. Med. 343, 450–456 (2000).
215. Zlokovic, B. V. Neurovascular mechanisms of Alzheimer’s neurodegeneration. Trends Neurosci. 28, 202–208 (2005).
216. Proitsi, P. et al. Genetic predisposition to increased blood cholesterol and triglyceride lipid levels and risk of Alzheimer disease: a Mendelian randomization analysis. PLoS Med. 11, e1001713 (2014).
217. Hassing, L. B. et al. Overweight in midlife and risk of dementia: a 40-year follow-up study. Int. J. Obes. 33, 893–898 (2009).
218. Anstey, K. J., Cherbuin, N., Budge, M. & Young, J. Body mass index in midlife and late-life as a risk factor for dementia: a meta-analysis of prospective studies. Obes. Rev. 12, e426–e437 (2011).
219. Christensen, A. & Pike, C. J. Menopause, obesity and inflammation: interactive risk factors for Alzheimer’s disease. Front. Aging Neurosci. 7, 130 (2015).
220. Letra, L., Santana, I. & Seica, R. Obesity as a risk factor for Alzheimer’s disease: the role of adipocytokines. Metab. Brain Dis. 29, 563–568 (2014).
221. Butterfield, D. A., Di Domenico, F. & Barone, E. Elevated risk of type 2 diabetes for development of Alzheimer disease: a key role for oxidative stress in brain. Biochimica et. Biophysica Acta 1842, 1693–1706 (2014).
222. Biessels, G. J., Strachan, M. W., Visseren, F. L., Kappelle, L. J. & Whitmer, R. A. Dementia and cognitive decline in type 2 diabetes and prediabetic stages: towards targeted interventions. Lancet 2, 246–255 (2014).
223. Moreira, P. I. High-sugar diets, type 2 diabetes and Alzheimer’s disease. Curr. Opin. Clin. Nutr. Metab. care 16, 440–445 (2013).
224. Correia, S. C. et al. Insulin signaling, glucose metabolism and mitochondria: major players in Alzheimer’s disease and diabetes interrelation. Brain Res. 1441, 64–78 (2012).
225. Moreira, P. I. Alzheimer’s disease and diabetes: an integrative view of the role of mitochondria, oxidative stress, and insulin. J. Alzheimer’s. Dis. 30(Suppl 2), S199–S215 (2012).
226. Li, G. et al. Effect of simvastatin on CSF Alzheimer disease biomarkers in cognitively normal adults. Neurology 89, 1251–1255 (2017).
227. Gold, M. et al. Rosiglitazone monotherapy in mild-to-moderate Alzheimer’s disease: results from a randomized, double-blind, placebo-controlled phase III study. Dement. Geriatr. Cogn. Disord. 30, 131–146 (2010).
228. Moonga, I., Niccolini, F., Wilson, H., Pagano, G. & Politis, M. Hypertension is associated with worse cognitive function and hippocampal hypometabolism in Alzheimer’s disease. Eur. J. Neurol. 24, 1173–1182 (2017).
229. Wharton, W. et al. The effects of ramipril in individuals at risk for Alzheimer’s disease: results of a pilot clinical trial. J. Alzheimer’s. Dis. 32, 147–156 (2012).
230. Bagyinszky, E. et al. Role of inflammatory molecules in the Alzheimer’s disease progression and diagnosis. J. Neurological Sci. 376, 242–254 (2017).
231. Latta, C. H., Brothers, H. M. & Wilcock, D. M. Neuroinflammation in Alzheimer’s disease; A source of heterogeneity and target for personalized therapy. Neuroscience 302, 103–111 (2015).
232. Phillips, E. C. et al. Astrocytes and neuroinflammation in Alzheimer’s disease. Biochemical Soc. Trans. 42, 1321–1325 (2014).
233. Santos, L. E., Beckman, D. & Ferreira, S. T. Microglial dysfunction connects depression and Alzheimer’s disease. Brain Behav. Immun. 55, 151–165 (2016).
234. McGeer, P. L., Itagaki, S. & McGeer, E. G. Expression of the histocompatibility glycoprotein HLA-DR in neurological disease. Acta Neuropathol 76, 550–557 (1988).
235. McGeer, E. G. & McGeer, P. L. Neuroinflammation in Alzheimer’s disease and mild cognitive impairment: a field in its infancy. J. Alzheimer’s. Dis. 19, 355–361 (2010).
236. Meda, L. et al. Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature 374, 647–650 (1995).
237. El Khoury, J. et al. Scavenger receptor-mediated adhesion of microglia to beta-amyloid fibrils. Nature 382, 716–719 (1996).
238. Weldon, D. T. et al. Fibrillar beta-amyloid induces microglial phagocytosis, expression of inducible nitric oxide synthase, and loss of a select population of neurons in the rat CNS in vivo. J. Neurosci. 18, 2161–2173 (1998).
239. Eikelenboom, P. & Stam, F. C. Immunoglobulins and complement factors in senile plaques. An immunoperoxidase study. Acta Neuropathol. 57, 239–242 (1982).
240. Michaud, M. et al. Proinflammatory cytokines, aging, and age-related diseases. J. Am. Med. Dir. Assoc. 14, 877–882 (2013).
241. Pluvinage, J. V. et al. CD22 blockade restores homeostatic microglial phagocytosis in ageing brains. Nature 568, 187–192 (2019).
242. Lyketsos, C. G. et al. Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial. Neurology 68, 1800–1808 (2007).
243. Qian, X. & Xu, Z. Fluorescence imaging of metal ions implicated in diseases. Chem. Soc. Rev. 44, 4487–4493 (2015).
244. Scott, L. E. & Orvig, C. Medicinal inorganic chemistry approaches to passivation and removal of aberrant metal ions in disease. Chem. Rev. 109, 4885–4910 (2009).
245. Que, E. L., Domaille, D. W. & Chang, C. J. Metals in neurobiology: probing their chemistry and biology with molecular imaging. Chem. Rev. 108, 1517–1549 (2008).
246. Santner, A. & Uversky, V. N. Metalloproteomics and metal toxicology of alpha-synuclein. Metallomics 2, 378–392 (2010).
247. Tamano, H. & Takeda, A. Dynamic action of neurometals at the synapse. Metallomics 3, 656–661 (2011).
248. Clements, A., Allsop, D., Walsh, D. M. & Williams, C. H. Aggregation and metal-binding properties of mutant forms of the amyloid A beta peptide of Alzheimer’s disease. J. Neurochem. 66, 740–747 (1996).
249. Duce, J. A. & Bush, A. I. Biological metals and Alzheimer’s disease: implications for therapeutics and diagnostics. Prog. Neurobiol. 92, 1–18 (2010).
250. Spinello, A., Bonsignore, R., Barone, G., Keppler, B. K. & Terenzi, A. Metal ions and metal complexes in Alzheimer’s disease. Curr. Pharm. Des. 22, 3996–4010 (2016).
251. Lovell, M. A., Robertson, J. D., Teesdale, W. J., Campbell, J. L. & Markesbery, W. R. Copper, iron and zinc in Alzheimer’s disease senile plaques. J. Neurol. Sci. 158, 47–52 (1998).
252. Dong, J. et al. Metal binding and oxidation of amyloid-beta within isolated senile plaque cores: Raman microscopic evidence. Biochemistry 42, 2768–2773 (2003).
253. Siotto, M., Bucossi, S. & Squitti, R. Copper status abnormalities and how to measure them in neurodegenerative disorders. Recent Pat. CNS Drug Discov. 5, 182–194 (2010).
254. Squitti, R. et al. Excess of nonceruloplasmin serum copper in AD correlates with MMSE, CSF [beta]-amyloid, and h-tau. Neurology 67, 76–82 (2006).
255. Roberts, B. R., Ryan, T. M., Bush, A. I., Masters, C. L. & Duce, J. A. The role of metallobiology and amyloid-beta peptides in Alzheimer’s disease. J. Neurochem. 120(Suppl 1), 149–166 (2012).
256. Sparks, D. L. & Schreurs, B. G. Trace amounts of copper in water induce beta-amyloid plaques and learning deficits in a rabbit model of Alzheimer’s disease. Proc. Natl Acad. Sci. USA 100, 11065–11069 (2003).
257. Bayer, T. A. et al. Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Abeta production in APP23 transgenic mice. Proc. Natl Acad. Sci. USA 100, 14187–14192 (2003).
258. Hua, H. et al. Toxicity of Alzheimer’s disease-associated Abeta peptide is ameliorated in a Drosophila model by tight control of zinc and copper availability. Biol. Chem. 392, 919–926 (2011).
259. Berg, D. & Youdim, M. B. Role of iron in neurodegenerative disorders. Top. Magn. Reson. Imaging 17, 5–17 (2006).
260. Rodrigue, K. M., Haacke, E. M. & Raz, N. Differential effects of age and history of hypertension on regional brain volumes and iron. NeuroImage 54, 750–759 (2011).
261. Callaghan, M. F. et al. Widespread age-related differences in the human brain microstructure revealed by quantitative magnetic resonance imaging. Neurobiol. Aging 35, 1862–1872 (2014).
262. Ward, R. J., Zucca, F. A., Duyn, J. H., Crichton, R. R. & Zecca, L. The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol. 13, 1045–1060 (2014).
263. Hare, D. J. et al. Is early-life iron exposure critical in neurodegeneration? Nat. Rev. 11, 536–544 (2015).
264. Goodman, L. Alzheimer’s disease; a clinico-pathologic analysis of twenty-three cases with a theory on pathogenesis. J. Nerv. Ment. Dis. 118, 97–130 (1953).
265. Bartzokis, G. et al. In vivo evaluation of brain iron in Alzheimer’s disease and normal subjects using MRI. Biol. Psychiatry 35, 480–487 (1994).
266. Bartzokis, G. & Tishler, T. A. MRI evaluation of basal ganglia ferritin iron and neurotoxicity in Alzheimer’s and Huntingon's disease. Cell. Mol. Biol. 46, 821–833 (2000).
267. Ding, B. et al. Correlation of iron in the hippocampus with MMSE in patients with Alzheimer’s disease. J. Magn. Reson. Imaging 29, 793–798 (2009).
268. Pfefferbaum, A., Adalsteinsson, E., Rohlfing, T. & Sullivan, E. V. MRI estimates of brain iron concentration in normal aging: comparison of field-dependent (FDRI) and phase (SWI) methods. NeuroImage 47, 493–500 (2009).
269. Luo, Z. et al. The correlation of hippocampal T2-mapping with neuropsychology test in patients with Alzheimer’s disease. PloS ONE 8, e76203 (2013).
270. Ghadery, C. et al. R2* mapping for brain iron: associations with cognition in normal aging. Neurobiol. Aging 36, 925–932 (2015).
271. Langkammer, C., Ropele, S., Pirpamer, L., Fazekas, F. & Schmidt, R. MRI for iron mapping in Alzheimer’s disease. Neurodegener Dis. 13, 189–191 (2014).
272. Tao, Y., Wang, Y., Rogers, J. T. & Wang, F. Perturbed iron distribution in Alzheimer’s disease serum, cerebrospinal fluid, and selected brain regions: a systematic review and meta-analysis. J. Alzheimer’s. Dis. 42, 679–690 (2014).
273. Belaidi, A. A. & Bush, A. I. Iron neurochemistry in Alzheimer’s disease and Parkinson's disease: targets for therapeutics. J. Neurochem. 139(Suppl 1), 179–197 (2016).
274. Lane, D. J. R., Ayton, S. & Bush, A. I. Iron and Alzheimer’s disease: an update on emerging mechanisms. J. Alzheimer’s. Dis. 64, S379–s395 (2018).
275. Ke, Y. & Ming Qian, Z. Iron misregulation in the brain: a primary cause of neurodegenerative disorders. Lancet Neurol. 2, 246–253 (2003).
276. Qian, Z. M. & Shen, X. Brain iron transport and neurodegeneration. Trends Mol. Med. 7, 103–108 (2001).
277. Qian, Z. M. & Wang, Q. Expression of iron transport proteins and excessive iron accumulation in the brain in neurodegenerative disorders. Brain Res. 27, 257–267 (1998).
278. Becerril-Ortega, J., Bordji, K., Freret, T., Rush, T. & Buisson, A. Iron overload accelerates neuronal amyloid-beta production and cognitive impairment in transgenic mice model of Alzheimer’s disease. Neurobiol. Aging 35, 2288–2301 (2014).
279. Rogers, J. T. et al. Iron and the translation of the amyloid precursor protein (APP) and ferritin mRNAs: riboregulation against neural oxidative damage in Alzheimer’s disease. Biochemical Soc. Trans. 36, 1282–1287 (2008).
280. Smith, M. A., Harris, P. L., Sayre, L. M. & Perry, G. Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc. Natl Acad. Sci. USA 94, 9866–9868 (1997).
281. Faux, N. G. et al. An anemia of Alzheimer’s disease. Mol. Psychiatry 19, 1227–1234 (2014).
282. Atkinson, A. & Winge, D. R. Metal acquisition and availability in the mitochondria. Chem. Rev. 109, 4708–4721 (2009).
283. Chung, S. D., Sheu, J. J., Kao, L. T., Lin, H. C. & Kang, J. H. Dementia is associated with iron-deficiency anemia in females: a population-based study. J. Neurol. Sci. 346, 90–93 (2014).
284. Dixit, R., Ross, J. L., Goldman, Y. E. & Holzbaur, E. L. Differential regulation of dynein and kinesin motor proteins by tau. Science 319, 1086–1089 (2008).
285. Binder, L. I., Frankfurter, A. & Rebhun, L. I. The distribution of tau in the mammalian central nervous system. J. Cell Biol. 101, 1371–1378 (1985).
286. Kempf, M., Clement, A., Faissner, A., Lee, G. & Brandt, R. Tau binds to the distal axon early in development of polarity in a microtubule-and microfilament-dependent manner. J. Neurosci. 16, 5583–5592 (1996).
287. Black, M. M., Slaughter, T., Moshiach, S., Obrocka, M. & Fischer, I. Tau is enriched on dynamic microtubules in the distal region of growing axons. J. Neurosci. 16, 3601–3619 (1996).
288. Liu, J. L., Fan, Y. G., Yang, Z. S., Wang, Z. Y. & Guo, C. Iron and Alzheimer’s disease: from pathogenesis to therapeutic implications. Front. Neurosci. 12, 632 (2018).
289. Exley, C. The aluminium-amyloid cascade hypothesis and Alzheimer’s disease. Sub-Cell. Biochem. 38, 225–234 (2005).
290. Zatta, P., Drago, D., Bolognin, S. & Sensi, S. L. Alzheimer’s disease, metal ions and metal homeostatic therapy. Trends Pharmacol. Sci. 30, 346–355 (2009).
291. Rogers, J. T. et al. Translation of the alzheimer amyloid precursor protein mRNA is up-regulated by interleukin-1 through 5'-untranslated region sequences. J. Biol. Chem. 274, 6421–6431 (1999).
292. Rogers, J. T. et al. An iron-responsive element type II in the 5'-untranslated region of the Alzheimer’s amyloid precursor protein transcript. J. Biol. Chem. 277, 45518–45528 (2002).
293. Tammela, T., Petrova, T. V. & Alitalo, K. Molecular lymphangiogenesis: new players. Trends Cell Biol. 15, 434–441 (2005).
294. Alitalo, K., Tammela, T. & Petrova, T. V. Lymphangiogenesis in development and human disease. Nature 438, 946–953 (2005).
295. Aspelund, A. et al. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J. Exp. Med. 212, 991–999 (2015).
296. Louveau, A. et al. Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337–341 (2015).
297. Absinta, M. et al. Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI. eLife 6. https://doi.org/10.7554/eLife.29738 (2017).
298. Sweeney, M. D., Sagare, A. P. & Zlokovic, B. V. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat. Rev. Neurol. 14, 133–150 (2018).
299. Zhao, Z. et al. Central role for PICALM in amyloid-beta blood-brain barrier transcytosis and clearance. Nat. Neurosci. 18, 978–987 (2015).
300. Yang, L. et al. Evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of CSF tracer. J. Transl. Med. 11, 107 (2013).
301. Thrane, A. S., Rangroo Thrane, V. & Nedergaard, M. Drowning stars: reassessing the role of astrocytes in brain edema. Trends Neurosci. 37, 620–628 (2014).
302. Iliff, J. J. & Nedergaard, M. Is there a cerebral lymphatic system? Stroke 44, S93–S95 (2013).
303. Jessen, N. A., Munk, A. S., Lundgaard, I. & Nedergaard, M. The glymphatic system: a beginner's guide. Neurochem. Res. 40, 2583–2599 (2015).
304. Shibata, M. et al. Clearance of Alzheimer’s amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J. Clin. Investig. 106, 1489–1499 (2000).
305. Iliff, J. J. et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci. Transl. Med. 4, 147ra111 (2012).
306. Mestre, H. et al. Aquaporin-4-dependent glymphatic solute transport in the rodent brain. eLife 7, https://doi.org/10.7554/eLife.40070 (2018).
307. Da Mesquita, S., Fu, Z. & Kipnis, J. The meningeal lymphatic system: a new player in neurophysiology. Neuron 100, 375–388 (2018).
308. Da Mesquita, S. et al. Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature 560, 185–191 (2018).
309. Sjogren, T., Sjogren, H. & Lindgren, A. G. Morbus Alzheimer and morbus pick; a genetic, clinical and patho-anatomical study. Acta Psychiatr. Neurol. Scand. Suppl. 82, 1–152 (1952).
310. Middleton, P. J., Petric, M., Kozak, M., Rewcastle, N. B. & McLachlan, D. R. Herpes-simplex viral genome and senile and presenile dementias of Alzheimer and pick. Lancet 1, 1038 (1980).
311. McNamara, J. & Murray, T. A. Connections between herpes simplex virus type 1 and Alzheimer’s disease pathogenesis. Curr. Alzheimer Res. 13, 996–1005 (2016).
312. Itzhaki, R. F. Herpes simplex virus type 1 and Alzheimer’s disease: increasing evidence for a major role of the virus. Front. Aging Neurosci. 6, 202 (2014).
313. Itzhaki, R. F. Herpes and Alzheimer’s disease: subversion in the central nervous system and how it might be halted. J. Alzheimer’s. Dis. 54, 1273–1281 (2016).
314. Carbone, I. et al. Herpes virus in Alzheimer’s disease: relation to progression of the disease. Neurobiol. Aging 35, 122–129 (2014).
315. Itzhaki, R. F. et al. Microbes and Alzheimer’s disease. J. Alzheimer’s. Dis. 51, 979–984 (2016).
316. Mastroeni, D. et al. Laser-captured microglia in the Alzheimer’s and Parkinson's brain reveal unique regional expression profiles and suggest a potential role for hepatitis B in the Alzheimer’s brain. Neurobiol. Aging 63, 12–21 (2018).
317. Itzhaki, R. F. Herpes simplex virus type 1 and Alzheimer’s disease: possible mechanisms and signposts. FASEB J. 31, 3216–3226 (2017).
318. Lovheim, H., Gilthorpe, J., Adolfsson, R., Nilsson, L. G. & Elgh, F. Reactivated herpes simplex infection increases the risk of Alzheimer’s disease. Alzheimers Dement. 11, 593–599 (2015).
319. Lovheim, H. et al. Herpes simplex infection and the risk of Alzheimer’s disease: a nested case-control study. Alzheimer’s. Dement. 11, 587–592 (2015).
320. Westman, G. et al. Decreased HHV-6 IgG in Alzheimer’s disease. Front. Neurol. 8, 40 (2017).
321. Readhead, B. et al. Multiscale analysis of independent Alzheimer’s cohorts finds disruption of molecular, genetic, and clinical networks by human herpesvirus. Neuron. 99, 64–82 (2018).
322. Kumar, D. K. et al. Amyloid-beta peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Sci. Transl. Med. 8, 340ra372 (2016).
323. Soscia, S. J. et al. The Alzheimer’s disease-associated amyloid beta-protein is an antimicrobial peptide. PloS ONE 5, e9505 (2010).
324. Mohr, A. M. & Mott, J. L. Overview of microRNA biology. Semin. Liver Dis. 35,3–11 (2015).
325. Woldemichael, B. T. & Mansuy, I. M. Micro-RNAs in cognition and cognitive disorders: potential for novel biomarkers and therapeutics. Biochemical Pharmacol. 104, 1–7 (2016).
326. Harden, J. T. & Krams, S. M. Micro-RNAs in transplant tolerance. Curr. Opin. Organ Transpl. 23, 66–72 (2018).
327. Ul Hussain, M. Micro-RNAs (miRNAs): genomic organisation, biogenesis and mode of action. Cell Tissue Res. 349, 405–413 (2012).
328. Wang, W. X. et al. The expression of microRNA miR-107 decreases early in Alzheimer’s disease and may accelerate disease progression through regulation of beta-site amyloid precursor protein-cleaving enzyme 1. J. Neurosci. 28, 1213–1223 (2008).
329. Hebert, S. S. et al. Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer’s disease correlates with increased BACE1/beta-secretase expression. Proc. Natl Acad. Sci. USA 105, 6415–6420 (2008).
330. Liu, B. et al. Preparation and identification of a series of mannose glucuronic acid oligosaccharides. Chem. J. Chin. Univ. 27, 485–487 (2006).
331. Gao, Y., Zhang, L. & Jiao, W. Marine glycan-derived therapeutics in China. Prog. Mol. Biol. Transl. Sci. 163, 113–134 (2019).
332. Kong, L. N. et al. Effects of acidic oligose on differentially expressed genes in the mice model of Alzheimer’s disease by microarray. Acta Pharm. Sin. 40, 1105–1109 (2005).
333. M, G. GV-971, a new drug against Alzheimer’s disease. Chin. J. Pharmacol Toxicol. 31, 459–460 (2017).
334. Mortimer, J. A. et al. Changes in brain volume and cognition in a randomized trial of exercise and social interaction in a community-based sample of nondemented Chinese elders. J. Alzheimer’s. Dis. 30, 757–766 (2012).
335. Fotenos, A. F., Snyder, A. Z., Girton, L. E., Morris, J. C. & Buckner, R. L. Normative estimates of cross-sectional and longitudinal brain volume decline in aging and AD. Neurology 64, 1032–1039 (2005).
336. Freeman, S. H. et al. Preservation of neuronal number despite age-related cortical brain atrophy in elderly subjects without Alzheimer disease. J. Neuropathol. Exp. Neurol. 67, 1205–1212 (2008).
337. Meyer, D., Bonhoeffer, T. & Scheuss, V. Balance and stability of synaptic structures during synaptic plasticity. Neuron 82, 430–443 (2014).
338. Spruston, N. Pyramidal neurons: dendritic structure and synaptic integration. Nat. Rev. Neurosci. 9, 206–221 (2008).
339. Hart, M. P. & Hobert, O. Neurexin controls plasticity of a mature, sexually dimorphic neuron. Nature 553, 165–170 (2018).
340. Sala-Llonch, R. et al. Inflammation, amyloid, and atrophy in the aging brain: relationships with longitudinal changes in cognition. J. Alzheimer’s. Dis. 58, 829–840 (2017).
341. Paz Soldan, M. M. et al. Correlation of brain atrophy, disability, and spinal cord atrophy in a murine model of multiple sclerosis. J. Neuroimaging 25, 595–599 (2015).
342. Last, N., Tufts, E. & Auger, L. E. The effects of meditation on grey matter atrophy and neurodegeneration: a systematic review. J. Alzheimer’s. Dis. 56, 275–286 (2017).
343. Moran, C. et al. Brain atrophy in type 2 diabetes: regional distribution and influence on cognition. Diabetes Care 36, 4036–4042 (2013).
344. Chapleau, M., Aldebert, J., Montembeault, M. & Brambati, S. M. Atrophy in Alzheimer’s disease and semantic dementia: an ALE meta-analysis of voxel-based morphometry studies. J. Alzheimer’s. Dis. 54, 941–955 (2016).
345. Pini, L. et al. Brain atrophy in Alzheimer’s disease and aging. Ageing Res. Rev. 30, 25–48 (2016).
346. Risacher, S. L. et al. Alzheimer disease brain atrophy subtypes are associated with cognition and rate of decline. Neurology 89, 2176–2186 (2017).
347. Allemang-Grand, R. et al. Altered brain development in an early-onset murine model of Alzheimer’s disease. Neurobiol. Aging 36, 638–647 (2015).
348. Jack, C. R. Jr. et al. Rate of medial temporal lobe atrophy in typical aging and Alzheimer’s disease. Neurology 51, 993–999 (1998).
349. Ingvar, D. H., Risberg, J. & Schwartz, M. S. Evidence of subnormal function of association cortex in presenile dementia. Neurology 25, 964–974 (1975).
350. Ferris, S. H. et al. Positron emission tomography in the study of aging and senile dementia. Neurobiol. Aging 1, 127–131 (1980).
351. Hirono, N., Kitagaki, H., Kazui, H., Hashimoto, M. & Mori, E. Impact of white matter changes on clinical manifestation of Alzheimer’s disease: a quantitative study. Stroke 31, 2182–2188 (2000).
352. Liu, Z. D., Zhang, S., Hao, J. J., Xie, T. R. & Kang, J. S. Cellular model of neuronal atrophy induced by DYNC1I1 deficiency reveals protective roles of RAS-RAF-MEK signaling. Protein Cell 7, 638–650 (2016).
353. Mizushima, N., Levine, B., Cuervo, A. M. & Klionsky, D. J. Autophagy fights disease through cellular self-digestion. Nature 451, 1069–1075 (2008).
354. Hayashi-Nishino, M. et al. A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation. Nat. Cell Biol. 11, 1433–1437 (2009).
355. Klionsky, D. J. Autophagy: from phenomenology to molecular understanding in less than a decade. Nat. Rev. Mol. Cell Biol. 8, 931–937 (2007).
356. Wirawan, E., Vanden Berghe, T., Lippens, S., Agostinis, P. & Vandenabeele, P. Autophagy: for better or for worse. Cell Res. 22, 43–61 (2012).
357. Mizushima, N. & Komatsu, M. Autophagy: renovation of cells and tissues. Cell 147, 728–741 (2011).
358. Wong, E. & Cuervo, A. M. Autophagy gone awry in neurodegenerative diseases. Nat. Neurosci. 13, 805–811 (2010).
359. Nixon, R. A., Yang, D. S. & Lee, J. H. Neurodegenerative lysosomal disorders: a continuum from development to late age. Autophagy 4, 590–599 (2008).
360. Winslow, A. R. & Rubinsztein, D. C. Autophagy in neurodegeneration and development. Biochimica et. Biophysica Acta 1782, 723–729 (2008).
361. Harris, H. & Rubinsztein, D. C. Control of autophagy as a therapy for neurodegenerative disease. Nat. Rev. Neurol. 8, 108–117 (2011).
362. Nixon, R. A. The role of autophagy in neurodegenerative disease. Nat. Med. 19, 983–997 (2013).
363. Komatsu, M. et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884 (2006).
364. Boland, B. et al. Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer’s disease. J. Neurosci. 28, 6926–6937 (2008).
365. Lee, S., Sato, Y. & Nixon, R. A. Lysosomal proteolysis inhibition selectively disrupts axonal transport of degradative organelles and causes an Alzheimer’s-like axonal dystrophy. J. Neurosci. 31, 7817–7830 (2011).
366. Salminen, A. et al. Impaired autophagy and APP processing in Alzheimer’s disease: the potential role of Beclin 1 interactome. Prog. Neurobiol. 106-107, 33–54 (2013).
367. Wang, L. et al. The cytoplasmic nuclear shuttling of Beclin 1 in neurons with Alzheimer’s disease-like injury. Neurosci. Lett. 661, 63–70 (2017).
368. Pickford, F. et al. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J. Clin. Investig. 118, 2190–2199 (2008).
369. Xiao, F. H. et al. Transcriptome evidence reveals enhanced autophagy-lysosomal function in centenarians. Genome Res. 28, 1601–1610 (2018).
370. Luo, R. et al. Activation of PPARA-mediated autophagy reduces Alzheimer disease-like pathology and cognitive decline in a murine model. Autophagy, 1–18. https://doi.org/10.1080/15548627.2019.1596488 (2019).
371. Kim, S. K. et al. ERK1/2 is an endogenous negative regulator of the gamma-secretase activity. FASEB J. 20, 157–159 (2006).
372. Cirrito, J. R. et al. Serotonin signaling is associated with lower amyloid-beta levels and plaques in transgenic mice and humans. Proc. Natl Acad. Sci. USA 108, 14968–14973 (2011).
373. Origlia, N., Arancio, O., Domenici, L. & Yan, S. S. MAPK, beta-amyloid and synaptic dysfunction: the role of RAGE. Expert Rev. Neurotherapeutics 9, 1635–1645 (2009).
374. Nicotra, A. et al. MAPKs mediate the activation of cytosolic phospholipase A2 by amyloid beta(25-35) peptide in bovine retina pericytes. Biochimica et. Biophysica Acta 1733, 172–186 (2005).
375. Zempel, H., Thies, E., Mandelkow, E. & Mandelkow, E. M. Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines. J. Neurosci. 30, 11938–11950 (2010).
376. Acosta-Cabronero, J. et al. Atrophy, hypometabolism and white matter abnormalities in semantic dementia tell a coherent story. Brain 134, 2025–2035 (2011).
377. La Joie, R. et al. Region-specific hierarchy between atrophy, hypometabolism, and beta-amyloid (Abeta) load in Alzheimer’s disease dementia. J. Neurosci. 32, 16265–16273 (2012).
378. Costantini, L. C., Barr, L. J., Vogel, J. L. & Henderson, S. T. Hypometabolism as a therapeutic target in Alzheimer’s disease. BMC Neurosci. 9(Suppl 2), S16 (2008).
379. Erecinska, M. & Silver, I. A. ATP and brain function. J. Cereb. Blood Flow. Metab. 9, 2–19 (1989).
380. Arnold, S. E. et al. Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nature reviews. Neurology 14, 168–181 (2018).
381. Cunha, R. A. & Ribeiro, J. A. ATP as a presynaptic modulator. Life Sci. 68, 119–137 (2000).
382. Cisneros-Mejorado, A., Perez-Samartin, A., Gottlieb, M. & Matute, C. ATP signaling in brain: release, excitotoxicity and potential therapeutic targets. Cell. Mol. Neurobiol. 35, 1–6 (2015).
383. Weise, C. M. et al. Left lateralized cerebral glucose metabolism declines in amyloid-beta positive persons with mild cognitive impairment. NeuroImage. Clin. 20, 286–296 (2018).
384. Croteau, E. et al. A cross-sectional comparison of brain glucose and ketone metabolism in cognitively healthy older adults, mild cognitive impairment and early Alzheimer’s disease. Exp. Gerontol. 107, 18–26 (2018).
385. Neth, B. J. & Craft, S. Insulin resistance and Alzheimer’s disease: bioenergetic linkages. Front. Aging Neurosci. 9, 345 (2017).
386. de Leon, M. J. et al. Positron emission tomographic studies of aging and Alzheimer disease. AJNR Am. J. Neuroradiol. 4, 568–571 (1983).
387. Di Domenico, F., Barone, E., Perluigi, M. & Butterfield, D. A. The triangle of death in Alzheimer’s disease brain: the aberrant cross-talk among energy metabolism, mammalian target of rapamycin signaling, and protein homeostasis revealed by redox proteomics. Antioxid. Redox Signal. 26, 364–387 (2017).
388. Szablewski, L. Glucose transporters in brain: in health and in Alzheimer’s disease. J. Alzheimer’s. Dis 55, 1307–1320 (2017).
389. Green, D. R. & Kroemer, G. The pathophysiology of mitochondrial cell death. Science 305, 626–629 (2004).
390. Danial, N. N. & Korsmeyer, S. J. Cell death: critical control points. Cell 116, 205–219 (2004).
391. Wallace, D. C., Fan, W. & Procaccio, V. Mitochondrial energetics and therapeutics. Annu. Rev. Pathol. 5, 297–348 (2010).
392. Mishra, P. & Chan, D. C. Metabolic regulation of mitochondrial dynamics. J. Cell Biol. 212, 379–387 (2016).
393. Kang, J. S. et al. Docking of axonal mitochondria by syntaphilin controls their mobility and affects short-term facilitation. Cell 132, 137–148 (2008).
394. Wallace, D. C. The mitochondrial genome in human adaptive radiation and disease: on the road to therapeutics and performance enhancement. Gene 354, 169–180 (2005).
395. van der Bliek, A. M., Sedensky, M. M. & Morgan, P. G. Cell biology of the mitochondrion. Genetics 207, 843–871 (2017).
396. Oyewole, A. O. & Birch-Machin, M. A. Mitochondria-targeted antioxidants. FASEB J. 29, 4766–4771 (2015).
397. Grimm, A., Mensah-Nyagan, A. G. & Eckert, A. Alzheimer, mitochondria and gender. Neurosci. Biobehav. Rev. 67, 89–101 (2016).
398. Swerdlow, R. H. et al. Mitochondria, cybrids, aging, and Alzheimer’s disease. Prog. Mol. Biol. Transl. Sci. 146, 259–302 (2017).
399. Cardoso, S., Seica, R. M. & Moreira, P. I. Mitochondria as a target for neuroprotection: implications for Alzheimer s disease. Expert Rev. Neurotherapeutics 17, 77–91 (2017).
400. Chetelat, G. et al. Atrophy, hypometabolism and clinical trajectories in patients with amyloid-negative Alzheimer’s disease. Brain 139, 2528–2539 (2016).
401. White, E., Mehnert, J. M. & Chan, C. S. Autophagy, metabolism, and cancer. Clin. Cancer Res. 21, 5037–5046 (2015).
402. Perez-Caballero, L., Torres-Sanchez, S., Bravo, L., Mico, J. A. & Berrocoso, E. Fluoxetine: a case history of its discovery and preclinical development. Expert Opin. Drug Discov. 9, 567–578 (2014).
403. Meltzer, C. C. et al. Serotonin in aging, late-life depression, and Alzheimer’s disease: the emerging role of functional imaging. Neuropsychopharmacology 18, 407–430 (1998).
404. Hajszan, T., MacLusky, N. J. & Leranth, C. Short-term treatment with the antidepressant fluoxetine triggers pyramidal dendritic spine synapse formation in rat hippocampus. Eur. J. Neurosci. 21, 1299–1303 (2005).
405. Vakili, K. et al. Hippocampal volume in primary unipolar major depression: a magnetic resonance imaging study. Biol. Psychiatry 47, 1087–1090 (2000).
406. Santarelli, L. et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, 805–809 (2003).
407. Chen, S., Owens, G. C., Crossin, K. L. & Edelman, D. B. Serotonin stimulates mitochondrial transport in hippocampal neurons. Mol. Cell. Neurosci. 36, 472–483 (2007).
408. Mendez-David, I. et al. Rapid anxiolytic effects of a 5-HT(4) receptor agonist are mediated by a neurogenesis-independent mechanism. Neuropsychopharmacology 39, 1366–1378 (2014).
409. Imoto, Y. et al. Role of the 5-HT4 receptor in chronic fluoxetine treatment-induced neurogenic activity and granule cell dematuration in the dentate gyrus. Mol. Brain 8, 29 (2015).
410. Reynolds, G. P. et al. 5-Hydroxytryptamine (5-HT)4 receptors in post mortem human brain tissue: distribution, pharmacology and effects of neurodegenerative diseases. Br. J. Pharmacol. 114, 993–998 (1995).
411. Sachs, B. D. & Caron, M. G. Chronic fluoxetine increases extra-hippocampal neurogenesis in adult mice. Int. J. Neuropsychopharmacol. 18, https://doi.org/10.1093/ijnp/pyu029 (2014).
412. Bath, K. G. et al. BDNF Val66Met impairs fluoxetine-induced enhancement of adult hippocampus plasticity. Neuropsychopharmacology 37, 1297–1304 (2012).
413. Jin, H. J. et al. Alleviative effects of fluoxetine on depressive-like behaviors by epigenetic regulation of BDNF gene transcription in mouse model of post-stroke depression. Sci. Rep. 7, 14926 (2017).
414. Nigam, S. M. et al. Exercise and BDNF reduce Abeta production by enhancing alpha-secretase processing of APP. J. Neurochem. 142, 286–296 (2017).
415. Farrelly, L. A. et al. Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3. Nature 567, 535–539 (2019).
416. Szasz, B. K. et al. Direct inhibitory effect of fluoxetine on N-methyl-D-aspartate receptors in the central nervous system. Biol. Psychiatry 62, 1303–1309 (2007).
417. Jin, L. et al. Long-term ameliorative effects of the antidepressant fluoxetine exposure on cognitive deficits in 3 x TgAD mice. Mol. Neurobiol. 54, 4160–4171 (2017).
418. Hashimoto, K. Activation of sigma-1 receptor chaperone in the treatment of neuropsychiatric diseases and its clinical implication. J. Pharmacol. Sci. 127, 6–9 (2015).
419. Matsuno, K., Matsunaga, K., Senda, T. & Mita, S. Increase in extracellular acet-ylcholine level by sigma ligands in rat frontal cortex. J. Pharmacol. Exp. Ther. 265, 851–859 (1993).
420. Hashimoto, K. Sigma-1 receptors and selective serotonin reuptake inhibitors: clinical implications of their relationship. Cent. Nerv. Syst. Agents Med. Chem. 9, 197–204 (2009).
421. Hayashi, T. & Su, T. P. Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival. Cell 131, 596–610 (2007).
422. 2+. Cell Calcium 52, 28–35 (2012).
423. Xie, T. R., Liu, C. F. & Kang, J. S. Sympathetic transmitters control thermogenic efficacy of brown adipocytes by modulating mitochondrial complex V. Signal Transduct. Target. Ther. 2, 17060 (2017).
424. Xie, Y., Liu, P.-P., Lian, Y.-J., Liu, H.-b., Kang, J.-S. The effect of selective serotonin reuptake inhibitors on cognitive function in patients with Alzheimer’s disease and vascular dementia: focusing on fluoxetine with long follow-up periods. Signal Transduct. Targeted Ther. https://doi.org/10.1038/s41392-019-0064-7 (2019).
425. Matrisciano, F. et al. Changes in BDNF serum levels in patients with major depression disorder (MDD) after 6 months treatment with sertraline, escitalo-pram, or venlafaxine. J. Psychiatr. Res. 43, 247–254 (2009).
426. Aboukhatwa, M., Dosanjh, L. & Luo, Y. Antidepressants are a rational complementary therapy for the treatment of Alzheimer’s disease. Mol. Neurodegener. 5, 10 (2010).
427. Kaether, C., Haass, C. & Steiner, H. Assembly, trafficking and function of gamma-secretase. Neurodegener. Dis. 3, 275–283 (2006).
428. Lu, P. et al. Three-dimensional structure of human gamma-secretase. Nature 512, 166–170 (2014).
429. Sun, L., Zhou, R., Yang, G. & Shi, Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Abeta42 and Abeta40 peptides by gamma-secretase. Proc. Natl Acad. Sci. USA 114, E476–E485 (2017).
430. Kelleher, R. J. 3rd & Shen, J. Presenilin-1 mutations and Alzheimer’s disease. Proc. Natl Acad. Sci. USA 114, 629–631 (2017).
431. Saura, C. A. et al. Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Neuron 42, 23–36 (2004).
432. De Strooper, B. et al. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 398, 518–522 (1999).
433. Zheng, J. et al. Conditional deletion of Notch1 and Notch2 genes in excitatory neurons of postnatal forebrain does not cause neurodegeneration or reduction of Notch mRNAs and proteins. J. Biol. Chem. 287, 20356–20368 (2012).
434. Ni, C. Y., Murphy, M. P., Golde, T. E. & Carpenter, G. gamma-Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science 294, 2179–2181 (2001).
435. Marambaud, P. et al. A presenilin-1/gamma-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. EMBO J. 21, 1948–1956 (2002).
436. Marambaud, P. et al. A CBP binding transcriptional repressor produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutations. Cell 114, 635–645 (2003).
437. Georgakopoulos, A. et al. Metalloproteinase/Presenilin1 processing of ephrinB regulates EphB-induced Src phosphorylation and signaling. EMBO J. 25, 1242–1252 (2006).
438. Lammich, S. et al. Presenilin-dependent intramembrane proteolysis of CD44 leads to the liberation of its intracellular domain and the secretion of an Abeta-like peptide. J. Biol. Chem. 277, 44754–44759 (2002).
439. May, P., Reddy, Y. K. & Herz, J. Proteolytic processing of low density lipoprotein receptor-related protein mediates regulated release of its intracellular domain. J. Biol. Chem. 277, 18736–18743 (2002).
440. Goodnick, P. J., Chaudry, T., Artadi, J. & Arcey, S. Women's issues in mood disorders. Expert Opin. Pharmacother. 1, 903–916 (2000).
441. Mazure, C. M. & Swendsen, J. Sex differences in Alzheimer’s disease and other dementias. Lancet Neurol. 15, 451–452 (2016).
442. Austad, S. N. & Fischer, K. E. Sex differences in lifespan. Cell Metab. 23, 1022–1033 (2016).
443. Brooks-Wilson, A. R. Genetics of healthy aging and longevity. Hum. Genet. 132, 1323–1338 (2013).
444. Breitner, J. C. et al. APOE-epsilon4 count predicts age when prevalence of AD increases, then declines: the Cache County Study. Neurology 53, 321–331 (1999).
445. Park, S., Choi, S. G., Yoo, S. M., Son, J. H. & Jung, Y. K. Choline dehydrogenase interacts with SQSTM1/p62 to recruit LC3 and stimulate mitophagy. Autophagy 10, 1906–1920 (2014).
446. Zhang, Y. et al. Listeria hijacks host mitophagy through a novel mitophagy receptor to evade killing. Nat. Immunol. 20, 433–446 (2019).
447. Chen, Z., Siraj, S., Liu, L. & Chen, Q. MARCH5-FUNDC1 axis fine-tunes hypoxia-induced mitophagy. Autophagy 13, 1244–1245 (2017).
448. Princely Abudu, Y. et al. NIPSNAP1 and NIPSNAP2 act as “Eat Me” signals for mitophagy. Dev. Cell 49, 509–525.e512 (2019).
449. Ha, J., Guan, K. L. & Kim, J. AMPK and autophagy in glucose/glycogen metabolism. Mol. Asp. Med. 46, 46–62 (2015).
450. Wan, W. et al. mTORC1 Phosphorylates Acetyltransferase p300 to Regulate Autophagy and Lipogenesis. Mol. Cell 68, 323–335.e326 (2017).
451. Zheng, M. et al. Inactivation of Rheb by PRAK-mediated phosphorylation is essential for energy-depletion-induced suppression of mTORC1. Nat. Cell Biol. 13, 263–272 (2011).
452. Levin-Salomon, V., Bialik, S. & Kimchi, A. DAP-kinase and autophagy. Apoptosis 19, 346–356 (2014).
453. Torres-Quiroz, F., Filteau, M. & Landry, C. R. Feedback regulation between autophagy and PKA. Autophagy 11, 1181–1183 (2015).
454. Su, H. et al. VPS34 acetylation controls its lipid kinase activity and the initiation of canonical and non-canonical autophagy. Mol. Cell 67, 907–921. e907 (2017).
455. Stadtman, E. R. Oxidation of free amino acids and amino acid residues in proteins by radiolysis and by metal-catalyzed reactions. Annu. Rev. Biochem. 62, 797–821 (1993).
456. Xu, W., Barrientos, T. & Andrews, N. C. Iron and copper in mitochondrial diseases. Cell Metab. 17, 319–328 (2013).
457. Delnomdedieu, M. et al. First-in-human safety and long-term exposure data for AAB-003 (PF-05236812) and biomarkers after intravenous infusions of escalating doses in patients with mild to moderate Alzheimer’s disease. Alzheimer’s. Res. Ther. 8, 12 (2016).